The role of inflammation in cardiovascular disease and diabetes (DM) has become increasingly evident. Especially, a combination of risk factors such as hypertension, obesity, DM, smoking, hyperlipidemia, and genetic predisposition create a proinflammatory environment that leads to endothelial (EC) dysfunction. This dysfunction is exacerbated by disturbed blood flow (d-flow) against the EC. In the physiological state, normal EC function is maintained with the release of anti-atherosclerotic signals stimulated by laminar/steady blood flow and high shear stress (s-flow). Our data show that p90RSK activation inhibits Sentrin/SUMO- specific proteases 2 (SENP2) de-SUMOylation activity and increases both p53 and ERK5-SUMOylation, which increases p53 nuclear export and enhances the apoptotic function of p53 and inhibits ERK5-transcriptional activity and its anti-inflammatory responses. The major hypothesis is that p90RSK activation in EC at atheroprone areas inhibits ERK5-dependent transcriptional activity and stimulates p53-SUMOylation thereby promoting EC inflammation and apoptosis, especially in DM. The experimental approach will be to define the mechanisms by which p90RSK regulates ERK5, p53, EC inflammation and apoptosis in Aims 1 and 2. In Aim 3 we will use mutants and inhibitory fragments generated in aims 1 and 2 in well-defined flow environments to prove that we can mitigate the harmful effects of d-flow by inhibiting p90RSK- and SENP2-mediated inflammation and apoptosis. In Aim 4 we will use genetic mouse models to evaluate the relative roles of p90RSK and SENP2 activity in atherosclerosis. We anticipate that specific d-flow and DM-dependent p90RSK activation and subsequent ERK5 and p53-SUMOylation make EC atheroprone. The proposed studies should provide significant new information regarding two important questions in d-flow and DM-related EC dysfunction: 1. The role of p90RSK activation on SENP2 de-sumoylation activity and subsequent EC apoptosis and inflammation, and 2. The role of p90RSK-mediated ERK5 phosphorylation on EC inflammation. The concept of p90RSK-SENP2 and p90RSK-ERK5 compartmentalization (nucleus vs cytosol) in atherosclerosis is novel and highlights the importance of post-translational mechanisms in disease pathogenesis. The proteins in these pathways should be attractive drug targets since they have unique features that distinguish them from other MAPK and signal events. We believe that our novel small molecule, specific p90RSK inhibitor, should provide a new therapeutic strategy for reducing atherosclerosis in DM.